title: Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C.
abstract: Loss of CD4 T cell help correlates with virus persistence during acute hepatitis C virus (HCV) infection, but the underlying mechanism(s) remain unknown. We developed a combined proliferation/intracellular cytokine staining assay to monitor expansion of HCV-specific CD4 T cells and helper cytokines expression patterns during acute infections with different outcomes. We demonstrate that acute resolving HCV is characterized by strong Th1/Th17 responses with specific expansion of IL-21-producing CD4 T cells and increased IL-21 levels in plasma. In contrast, viral persistence was associated with lower frequencies of IL-21-producing CD4 T cells, reduced proliferation and increased expression of the inhibitory receptors T cell immunoglobulin and mucin-domain-containing-molecule-3 (Tim-3), programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) on HCV-specific CD8 T cells. Progression to persistent infection was accompanied by increased plasma levels of the Tim-3 ligand Galectin-9 (Gal-9) and expansion of Gal-9 expressing regulatory T cells (Tregs). In vitro supplementation of Tim-3(high) HCV-specific CD8 T cells with IL-21 enhanced their proliferation and prevented Gal-9 induced apoptosis. siRNA-mediated knockdown of Gal-9 in Treg cells rescued IL-21 production by HCV-specific CD4 T cells. We propose that failure of CD4 T cell help during acute HCV is partially due to an imbalance between Th17 and Treg cells whereby exhaustion of both CD4 and CD8 T cells through the Tim-3/Gal-9 pathway may be limited by IL-21 producing Th17 cells or enhanced by Gal-9 producing Tregs.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Hôpital St-Luc, Montréal, Québec, Canada.
authors.forename: Hassen
authors.initials: H
authors.lastname: Kared
authors.forename: Thomas
authors.initials: T
authors.lastname: Fabre
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bédard
authors.forename: Julie
authors.initials: J
authors.lastname: Bruneau
authors.forename: Naglaa H
authors.initials: NH
authors.lastname: Shoukry
mesh_terms: D000208:Acute Disease; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005500:Follow-Up Studies; D037161:Galectins / Q000096:biosynthesis / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D000072597:Hepatitis A Virus Cellular Receptor 2; D006526:Hepatitis C / Q000097:blood / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007378:Interleukins / Q000097:blood / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000098546:Interleukin-21
chemical_list: D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D007378:Interleukins; C105032:LGALS9 protein, human; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000098546:Interleukin-21